N-(4,4-diloweralkoxybutyl)-benzene sulfonamides



United States Patent ice Patented i 1133 R is selected from the group consisting of alkyl, halo- 3,501,526 gen, nitro, amino and acylarmno, ggggfi ai ggg Y is selected from the group consisting of oxygen and Peter H. L. Wei, Upper Darby, and Stanley C. Bell, :l and Philadelphia, Pa., assignors to American Home Prod- 5 R Selected P the group conslstltlg of f ucts Corporation, New York, N.Y., a corporation of Vlded that R3 13 other than y dlalkylamlhoalkyl; Delaware alkoxyalkyl; alkylthioalkyl; phenyl; halophenyl; benzyl; No Drawing. Original application Jan. 21, 1966, Ser. No. haloalkylphenyl; thienyl; furyl; thiazolinyl; cycloalkyl; 536,479, Patent dated July 1, and a second p-substituted-phenylsulfonyl pyrrolidine gggllzlzgged and this application Feb. 3, 1969,, Ser. 10 group of the Similar general f l Int. (:1. C07c 143/50 t 2 US. Cl. 260-556 2 Claims I I This is a division of application Ser. No. 536,479, noW N SC R3 US. Patent No. 3,453,289, July 1, 1969, filed Ian. 21, 15 k/ 1966.

This invention relates generally to 2-substituted l-arylsulfonyl pyrrolidine compounds and to starting materials h i however, e is ifi ll lk l b R1 R for preparing the former, and, more particularly, to novel R R R d Y are h as d fi d b P'suhstituted-phehylsulfohyl PYrfOhdine derivatives The p-substituted-phenylsulfonamide derivatives of the phefmaeolegleal activity, h t Valuable ifltefmediinvention which are particularly useful as intermediates ates Preparing Sald hovel deflvatlvesin the preparation of the compounds of Formula A above The novel Pharmacologieelly acttVe p- 'p are those having the following general formula: ylsulfonyl pyrrolidine derivatives encompassed by the present invention are those having the following general formula: R1 R A. R2 R1 R3- SO2NH(CH2)3CH(OR )g l l R SO N Y-R F wherein: R R

\/ R R R R and R are as defined for the compounds of Formula A above; and wherein: R is alkyl. R and R are each selected from the group consisting The general Syntheses of the Compounds of Formulae of hydrogen, alkyl, halogen, nitro and acylamino; A and B above are represented schematically below R and R are each selected from the group consisting of wherein R R4, R6 and R7 have the Same hydrogen, alkyl, halogen, nitro, amino and acylamino; meanings as in said formulae:

2 R1 2 1 1 l l R GSO C1+HzN(CHz)aCH(OR')2 mQsommommmonm l l l R R (I) (II) R R (III) H+ I R3 SO2N O-R ,t, R, U

R2 R1 R1 R2 I HOCHzCHzOH I I (VII) In preparing the compounds of the invention, a phenylsulfonyl chloride (I) in an inert solvent such as dimethoxyethane is added to a cold solution of an amino-acetal (II). The reaction solution is stirred, benzene is added and the mixture is then extracted with water. The organic layer is dried and the solvent is removed under reduced pressure to give the 'benzenesulfonamide denoted by Formula III. Treament of this compound in alcohol with mineral acid causes ring closure to form the pyrrolidine (IV).

The bis compounds denoted by Formula V are prepared by dissolving the sulfonamide compounds of Formula III in ethylene glycol (or ethylene dithiol when the thio analogs are desired) containing a trace of a mineral acid as hydrochloric acid and heating to around 50 to 80 C. The resulting product precipitates upon standing overnight and can be recrystallized from benzene.

Treatment of compounds of Formula III with a mercapto-tertiary amine in the presence of a mineral acid yields the 2-dialkylaminoalkylthio compounds of Formula VI. Similarly, treatment of said compounds of Formula III with a thiophenol yields the corresponding Z-phenylthiopyrrolidine compounds. In like manner, treatment of compounds of Formula III in acid medium with a mercapto-thiazine gives the corresponding 2-thiazinylthiopyrrolidine compounds (VII).

It has been discovered that compounds of Formula A, meeting the described qualifications, have useful pharmacological properties. More specifically, said compounds have been found to exhibit utility as central nervous system, diuretic and antiviral agents.

When the compounds of Formula A are employed for their central nervous system, diuretic and antiviral activity in mammals, they may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing conventional excipients, or in the form of solutions; or they may be injected parenterally, that is intramuscularly, iritravenously or subcutaneously. For parenteral administration they may be used in the form of sterile solutions containing other solutes, for example, enough saline or glucose to make the solutions isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford eifective results without causing any harmful or deleterious side effects and preferably at a level that is in the range of from about 0.1 mg. to about 7 mg. per kg. of body weight per day, although as aforementioned variations will occur. However, a dosage level that is in therange of from about 0.2 mg. to about 2 mg. per kg. of body weight per day is most desirably employed in order to achieve effective results.

The following examples are given by way of illustration.

EXAMPLE I p-Nitro-N(4,4-diethoxybutyl)-benzenesulfonamide p-Nitrobenzenesulfonyl chloride (22.10 g. or 0.10 m.) was slowly added to a cold dimethoxyethane solution of 'y-aminobutyraldehyde diethyl acetal (19.30 g. 0.12 111.) containing 20 g. of triethylarnine. After the solution was stirred for 20 minutes, benzene was added, followed by extraction of Water. After the organic layer was dried over anhydrous magnesium Sulfate, the solvent was removed at reduced pressure. The residue was recrystallized from a mixture of benzene and cyclohexane, M.P. 58-60 C.

Elemental analysis confirmed the empirical formula for C14H22N205S.

EXAMPLE II 2-ethoxy-1- (p-nitrophenylsulfonyl)pyrrolidine p Nitro (4,4-diethoxybutyl)-benzenesulfonamide (10.0 g.), prepared in accordance with Example I, was dissolved in ethyl alcohol. The solution was heated on a steam bath, in the presence of a few drops of cone. hydrochloric acid, for 10 min. The solution was cooled and the solid was collected. The compound can be recrystallized from n-hexane, M.P. 70-2 C.

Elemental analysis confirmed the empirical formula for C H N O S.

EXAMPLE III p-Bromo-N- (4,4-diethoxyybutyl) -benzenesulfonamide p-Bromobenzenesulfonyl chloride (10.20 g. or 0.04 m.) was slowly added to a cold dimethoxyethane solution of 'y-aminobutyraldehyde diethyl acetal (8.0 g. or 0.05 111.), containing 10 g. of triethyl amine. After the solution was stirred for 20 min., benzene was added, followed by extraction of water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed at reduced pressure. The residual solid was recrystallized from cyclohexane to give 13 g. of material, M.P. 87- 8 C.

Elemental analysis confirmed the empirical formula for C14H22BI'NO4S.

EXAMPLE IV 1-(p-bromophenylsulfonyl)-2-ethoxypyrrolidine p Bromo N-(4,4-diethoxybutyl)-benzenesulfonamide (10 g.) of Example III was dissolved in 30 ml. of ethyl alcohol and the solution heated on a steam bath for 30 min. in the presence of 8 drops of cone. hydrochloric acid. After the solvent was removed at reduced pressure, ;he residue was recrystallized from cyclohexane, M.P.

Elemental analysis confirmed the empirical formula for C12H16BI'NO3S.

EXAMPLE V 2,2-ethylenedioxybis[1-(p-bromophenylsulfonyl)- pyrrolidine] p-Bromo-N- (4,4-diethoxybutyl) -benzenesulfonamide of Example III (12.0 g. or 0.0313 111.) was dissolved in 50 ml. of ethylene glycol and heated on a steam bath, in the presence of 5 drops of hydrochloric acid,'for 1 hour. The solution was let stand at room temperature overnight. The solid was collected and washed with ethyl alcohol. 8.0 g. was obtained. The compound was recrystallized from benzene, M.P. 188-190 C.

Elemental analysis confirmed the empirical formula for C H Br N O S EXAMPLE VI 1-p-aminophenylsulfonyl-2-ethoxypyrrolidine The amino compound is prepared from the correspondmg l-p-nitro compound by catalytic hydrogenation using a platinum oxide catalyst.

EXAMPLE VII 1-( p-bromophenylsulfonyl) -2- [2- (diethylamino ethylthio] pyrrolidine hydrochloride p-Bromo-N-(4,4-diethoxybutyl -benzenesulfonamide of Example III (3.80 g. or 0.01 m,) and N,N-diethylamino ethanethiol hydrochloride (2.50 g. or 0.015 m.) were dissolved in 50 ml. of isopropyl alcohol and the solution heated on a steam bath, in the presence of 1 drop of cone. hydrochloride, for 3 hours. The solution was concentrated at reduced pressure and the residue recrystallized from isopropyl alcohol, M.P. 1278 C.

Elemental analysis confirmed the empirical formula for C1SHZ5BI'N2OZSZ'HCI.

EXAMPLE VIII 1- (p-bromophenylsulfonyl -2-( 2-thiazolin-2-yl-thio) pyrrolidine p-Bromo-N-(4,4-diethoxybutyl)-benzenesulfonamide of Example III (10.0 g. or 0.0263 m.) and Z-mercaptothiazoline (5.0 g. or 0.0425 m.) were dissolved in dioxane and the solution heated on a steam bath for 30 minutes in the presence of a few drops of concentrated HCl. A small amount of insoluble material was filtered off and the filtrate concentrated. The residue was recrystallized from dioxane to give 5.10 g., M.P. l835 C.

Elemental analysis confirmed the empirical formula for C13H15B1'N202S3.

EXAMPLE IX p-Acetamido-N-(4,4-diethoxybutyl)benzenesulfonamide p-Acetamidobenzenesulfonyl chloride (27.5 g. or 0.118 m.) was gradually added to a cold dimethoxyethane solution of 'y-aminobutyraldehyde diethyl acetal, containing 12.7 g. of triethylamine. The solution was stirred for 2 hours. Benzene was added and the solution extracted with water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed at a reduced pressure. The residue was recrystallized from isopropanol to give 26.0 g., M.P. 102-4" C.

Elemental analysis confirmed the empirical formula for C H N O S.

EXAMPLE X 4- 2-ethoxyl-pyrrolidinylsulfonyl) -acetanilide p-Acetamido N (4,4-diethoxybutyl)-benzenesulfonamide (8.00 g. or 0.0223 m.), prepared as in Example IX, was dissolved in C H OH and the solution was let stand at room temperature in the presence of 5 drops of conc. hydrochloric acid. The solid was collected and rinsed with ethyl alcohol. This gave 4.50 g. of a solid melting at l135 C.

Elemental analysis confirmed the empirical formula for C14H20N2O4S.

EXAMPLE XI 1- (p-chloro-o-toluenesulfonyl -2-ethoxypyrrolidine A dimethoxyethane solution of p-chloro-o-toluenesulfonyl chloride is slowly added to a cold solution of 'y-aminobutyraldehyde dimethyl acetal and triethylamino in the same solvent. The mixture is stirred for 15 minutes and benzene is then added. The resulting benzene solution is first washed with water and then dried over anhydrous magnesium sulfate. After the drying agent is removed, benzene is removed at reduced pressureThe residue is then dissolved in ethanol. After a few drops of hydrochloric acid are added to the ethanol solution, the latter is left to stand at room temperature overnight. Ethanol is thereafter removed at reduced pressure, and the resulting residue is recrystallized from ethanol to give 1-(p-chloro-o-toluenesulfonyl)-2-ethoxypyrrolidine.

EXAMPLE XII 1-p-ethylphenylsulfonyl-2-ethylthioethylthiopyrrolidine The above compound is prepared by reacting N-(4,4 diethoxybutyl)-p-ethylbenzenesulfonamide with 2'-ethylthioethyl mercaptan according to the procedure of Example IV.

6 EXAMPLE XIII l-p-bromophenylsulfonyl-2-phenylthiopyrrolidine The above compound is prepared by reacting p-bromo- N-(4,4-diethoxybutyl) benzenesulfonamide with thiophenyl according to the procedure of Example IV.

EXAMPLE XIV 1-p-tolylsulfonyl-2-cyclohexyloxy-pyrrolidine The title compound is prepared by reacting N-(4,4- diethoxybutyl)-p-tolylsulfonamide with cyclohexanol according to the procedure of Example IV.

EXAMPLE xv 2,2'-ethylenedithiobis-(2,4-dimethylbenzenesulfonylpyrrolidine) The above compound is prepared by reacting N-(4,4- diethoxybutyl) 2,4 dimethylbenzenesulfonamide with ethylenedithiol according to the procedure of Example V.

EXAMPLE XVI m-Chloro-N- (4,4-diethoxybutyl -p-toluenesulfonamide By following the procedure of Example I and using m-chloro-p-toluenesulfonyl chloride instead of p-nitrobenzenesulfonyl chloride as starting material, the above compound is prepared.

EXAMPLE XVII 1- m-chloro-p-toluenesulfonyl) -2-ethoxypyrrolidine By following the procedure of Example II, but substituting m chloro N (4,4 diethoxybutyl) p toluenesulfonamide as starting material, the above compound is prepared.

EXAMPLE XVIII EXAMPLE XXI 1-(m-amino-p-chloro-o-toluenesulfonyl)-2- ethoxypyrrolidine By following the procedure of Example II and substituting m amino p chloro N (4,4 diethoxybutyl) o-toluenesulfonamide as starting material, the above compound is obtained.

We claim:

1. A compound of the formula:

wherein R and R are each selected from the group consisting of hydrogen, lower alkyl, halogen, nitro and lower 7 8 alkanoylamino; R and R are each selected from the References Cited group consisting of hydrogen, lower alkyl, halogen, nitro, UNITED STATES PATENTS amino and lower alkanoylamino; R is halogen and Z is NH(CH2)3CH(OR7)2 wherein R7 is lower alkyL 3,453,239 7/1969 W61 (it al 260-32682 2. A compound as defined in claim 1 Wh1ch 1s: 5 HENRY R. LES, Primary Examiner p bromo N (4,4 diethoxybutyl) benzenesulfonamide. C. M. SHURKO, Assistant Examiner 

1. A COMPOUND OF THE FORMULA: 